1. Field of the Invention
The present invention relates to the manufacture of N-acyl derivatives of hydroxyarylglycines and to novel products resulting therefrom.
2. Description of the Prior Art
The hydroxyarylglycines and particularly D-p-hydroxyphenylglycine are at present used in the manufacture of semi-synthetic penicillins. For this use, whether for the separation of enanthiomorphs or for reaction with penicillins, the --NH.sub.2 group has to be protected by a group easily hydrolysable subsequently, for example an acyl group. The N-acyl derivatives of hydroxyarylglycines or N-2-acylamido-2-(hydroxyaryl) acetic acids hence constitute valuable intermediate products in the preparation of semi-synthetic penicillins. They are usually obtained by acylation of the corresponding hydroxyarylglycines, themselves prepared by the conventional methods of amino acid synthesis.
Among these methods, that of STRECKER and its modification, the method of BUCHERER, have been employed for a long time. They consist essentially of reacting an aldehyde, in the first case, with an alkali cyanide and ammonia, to obtain an .alpha.-aminoitrile, in the second case, with an alkali cyanide and ammonium carbonate to obtain a hydantoin, this nitrile or this hydantoin being then hydrolysed in an acid medium (ULLMANNS ENCYKLOPADIE DER TECHNISCHEN CHEMIE- Vol. 3, page 507). They have the drawback of being rather long and complicated and especially of using as a raw material, an aromatic aldehyde, which is an expensive substance.
A simpler method of synthesizing hydroxyarylglycines consists of condensing by a Mannich reaction, glyoxylic acid with a phenol and ammonia (French Pat. Nos. 71 25034 and 71 36918). The yields of this condensation are not very high and they are further reduced by the need to acylate the product obtained.
Recently, it has been proposed, to avoid the additional step constituted by protecting the -NH.sub.2 group, to synthesize directly hydroxyarylglycines whose nitrogen is protected. A first process consists of reacting glyoxylic acid with phenol and a nitrogen compound such as a carbamate, a thiocarbamate, a urea derivative or an amide (French Pat. Application No. 74 38338) in which the nitrogen is already protected. However, this method, for which moreover only examples with carbamates are given, leads, with phenols whose ortho and para positions are free, to mixtures of derivatives including .alpha.-aminoacetic groups at the ortho and para positions with yields which, to applicants' knowledge, are apparently uninteresting from the industrial point of view.
A second process consists of preparing in a first phase in an organic solvent medium, an adduct product of glyoxylic acid with an aromatic amide (U. ZOLLER and D. BEN ISHAI -- Tetrahedron -- Vol. 31 -- p. 863-866 (1975)) then of condensing this product with a hydroxyaryl compound in an acetic acid/sulfuric acid medium (D. BEN ISHAI, I. SATATI and Z. BERLER -- J.C.S. Chem. Comm -- No. 9 -- 7/5/75 p. 349). The latter process, if it enables satisfactory yields to be obtained, has the drawback of using aromatic amides which are not manufactured industrially and of fixing an acyl residue which is uselessly heavy and expensive, since it is destined to disappear in the course of the subsequent yields of the N-acyl derivative. In addition, it applies glyoxylic acid in the form of the hydrate, a product which is expensive and which is not manufactured industrially either.
This process using sulfuric acid or a mixture of acetic acid/sulfuric acid as the reaction medium is not usable when an amide is used which is an aliphatic amide as a result of the solubility of the final product in the reaction medium and the difficulty of extracting it.